T-cell large granular lymphocytic leukemia: treatment experience with fludarabine

OBJECTIVES: The aim of this retrospective study was to investigate the results of T-cell large granular lymphocytic leukemia treatment with fludarabine by assessing the complete hematologic response, the complete molecular response, progression-free survival, and overall survival. METHODS: We evaluated the records of six patients with T-cell large granular lymphocytic leukemia who were treated with fludarabine as a first-, second-, or third-line therapy, at a dose of 40 mg/m(2), for three to five days per month and 6 to 8 cycles. RESULTS: Of the six patients investigated with T-cell large granular lymphocytic leukemia who were treated with fludarabine, five (83.3%) were female, and their median age was 36.5 years (range 18 to 73). The median lymphocyte level was 3.4x10(9)/L (0.5 to 8.9). All patients exhibited a monoclonal T-cell receptor gamma gene rearrangement at diagnosis. Two (33.3%) patients received fludarabine as first-line treatment, two (33.3%) for refractory disease, one (16.6%) for relapsed disease after the suspension of methotrexate treatment due to liver toxicity, and one (16.6%) due to dyspesia. A complete hematologic response was achieved in all cases, and a complete molecular response was achieved in five out six cases (83.3%). During a mean follow-up period of 12 months, both the progression-free survival and overall survival rates were 100%. CONCLUSION: T-cell large granular lymphocytic leukemia demonstrated a high rate of complete hematologic and molecular response to fludarabine, with excellent compliance and tolerability rates. To confirm our results in this rare disease, we believe that fludarabine should be tested in clinical trials as a first-line treatment for T-cell large granular lymphocytic leukemia.

Salivary Cortisol, Alpha-Amylase and Heart Rate Variation in Response to Dental Treatment in Children

Objective. Anxiety and stress are usually related to the dental treatment situation. The objective was to investigate salivary cortisol and alpha-amylase levels (salivary biomarkers) and heart rate in children undergoing a minor dental procedure (dental prophylaxis). Study design. In total, 31 children (range 84-95 months) of both genders without caries or history of dental treatment/pain/trauma were selected. Three saliva samples were gathered: one prior to dental prophylaxis, one immediately after, and one ten minutes later Weight and height were assessed, and heart rate was evaluated prior to and during the procedure. Data were analyzed by correlation tests and t-test/Wikoxon (alpha=0.05). Results. Higher cortisol and amylase levels were observed before prophylaxis compared to afterward. Cortisol and amylase levels did not show a significant correlation, nor did salivary biomarkers and body mass index. However, heart rate and amylase levels showed a significant positive correlation. Conclusions. In the studied sample, certain anticipation of the dental treatment was observed because higher cortisol and amylase levels were observed before, rather than after, the event; moreover, a significant correlation between amylase levels and heart rate was observed. Thus, salivary biomarkers may be a valuable tool for evaluating anxiety-producing events, such as dental treatment, in children.

beta-ADRENOCEPTORS IN THE MEDIAL AMYGDALOID NUCLEUS MODULATE THE TACHYCARDIAC RESPONSE TO RESTRAINT STRESS IN RATS

In the present study, we investigated the involvement of beta-adrenoceptors in the medial amygdaloid nucleus (MeA) in cardiovascular responses evoked in rats submitted to an acute restraint stress. We first pretreated Wistar rats with the nonselective beta-adrenoceptor antagonist propranolol microinjected bilaterally into the MeA (10, 15, and 20 nmol/100 nL) 10 min before exposure to acute restraint. The pretreatment with propranolol did not affect the blood pressure (BP) increase evoked by restraint. However, it increased the tachycardiac response caused by acute restraint when animals were pretreated with a dose of 15 nmol, without a significant effect on the BP response. This result indicates that beta-adrenoceptors in the MeA have an inhibitory influence on restraint-evoked heart rate (HR) changes. Pretreatment with the selective beta(2)-adrenoceptor antagonist ICI 118,551 (10, 15, and 20 nmol/100 nL) significantly increased the restraint-evoked tachycardiac response after doses of 15 and 20 nmol, an effect that was similar to that observed after the pretreatment with propranolol at a dose of 15 nmol, without a significant effect on the BP response. Pretreatment of the MeA with the selective beta(1)-adrenoceptor antagonist CGP 20712 (10, 15, and 20 nmol/100 nL) caused an opposite effect on the HR response, and a significant decrease in the restraint-evoked tachycardia was observed only after the dose of 20 nmol, without a significant effect on the BP response. Because propranolol is an equipotent antagonist of both beta(1) and beta(2)-adrenoceptors, and opposite effects were observed after the treatment with the higher doses of the selective antagonists ICI 118,551 and CGP 20712, the narrow window in the dose-response to propranolol could be explained by a functional antagonism resulting from the simultaneous inhibition of beta(1) and beta(2)-adrenoceptors by the treatment with propranolol. The present results suggest that beta(2)-adrenoceptors have an inhibitory influence on the restraint-evoked tachycardiac response, whereas beta(1)-adrenoceptors have a facilitatory influence on the restraint-evoked tachycardiac response. (c) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Maturation of mononuclear phagocytes in the lungs of young calves-In vitro study

The influences of age in calves' immune system are described in their first phase of life. We hypothesized that variations that occur in the main mechanisms of lung innate response can help to identify periods of greater susceptibility to the respiratory diseases that affect calves in the first stage of their life. This study aimed to evaluate the innate immune system. Nine healthy calves were monitored for 3 mo and 8 immunologic evaluations were performed. Bronchoalveolar lavage samples were recovered by bronchoscopy. The alveolar macrophages in samples were identified by protein expression of cluster of differentiation 14 (CD14) and underwent functional evaluation of phagocytosis (Staphylococcus aureus stained with propidium iodide and Escherichia coli). Data was assessed by one-way ANOVA (unstacked and parametric) and the Mann-Whitney test (nonparametric). Functional alterations in CD14-positive phagocytes were observed, with punctual higher intensity of phagocytosis in the third week and its decrease starting at 45 d of life. A gradual increase in phagocytosis rate was observed starting at this date. It is concluded that from 45 d of life on, alveolar macrophages have less phagocytic capacity but more cells perform this function. We suggest that this occurs because lung macrophages of calves start to maintain their immune response without passive immunity influence. Until 90 d of life, calves did not achieve the stability to conclude the maturation of local innate immune response.

Effects of light intensity and temperature on Cylindrospermopsis raciborskii (Cyanobacteria) with straight and coiled trichomes: growth rate and morphology

Cylindrospermopsis raciborskii (Woloszynska) Seenayya et Subba Raju (Ordem Nostocales) is one of the most troublesome bloom-forming species in Brazil. Understanding the population dynamics of the different morphotypes of C. raciborskii (straight and coiled) could assist in the prediction of favourable conditions for the proliferation of this potentially toxin-producing species. The aim of the present study was to assess the effects of two different light intensities and temperatures on the growth rate and morphology of the trichomes of the straight and coiled morphotypes. For such, two non-toxin producing strains of C. raciborskii were used - one with a coiled trichome (ITEP31) and another with a straight trichome (ITEP28). The strains were cultured in BG-11 medium in a climatic chamber under controlled conditions. Two light intensities (30 and 90 mu mol.m(-2).s(-1)) were combined at temperatures of 21 and 31 degrees C and the growth rate and morphological changes were analysed. The morphotypes responded differently to the different temperatures and light intensities. Both strains exhibited faster growth velocities when submitted to higher light intensity and temperature. The lower temperature and higher luminosity hampered the development of both strains. Variations in cellular morphology and an absence of akinetes in both strains were related to the lower temperature (21 C). The coiled morphotype demonstrated considerable phenotype plasticity, changing the morphology of trichome throughout its growth curve. Although molecular analysis does not sustain the separation of the morphotypes as distinct species, their different eco-physiological responses should be considered further knowledge of extreme importance for the population control of these potentially toxic organisms.

Soil-nutrient availability modifies the response of young pioneer and late successional trees to elevated carbon dioxide in a Brazilian tropical environment

The aim of this work was to determine the impact of three levels of [CO2] and two levels of soil-nutrient availability on the growth and physiological responses of two tropical tree species differing in their ecological group: Croton urucurana Baillon, a pioneer (P), and also Cariniana legalis (Martius) Kuntze, a late succession (LS). We aimed to test the hypothesis that P species have stronger response to elevated [CO2] than LS species as a result of differences in photosynthetic capacity and growth kinetics between both functional groups. Seedlings of both species were grown in open-top-chambers under high (HN) or low (LN) soil-nutrient supply and exposed to ambient (380 mu mol mol(-1)) or elevated (570 and 760 mu mol mol(-1)) [CO2]. Measurements of gas exchange, chlorophyll a fluorescence, seedling biomass and allocation were made after 70 days of treatment. Results suggest that elevated [CO2] significantly enhances the photosynthetic rates (A) and biomass production in the seedlings of both species, but that soil-nutrient supply has the potential to modify the response of young tropical trees to elevated [CO2]. In relation to plants grown in ambient [CO2], the P species grown under 760 mu mol mol(-1) [CO2] showed increases of 28% and 91% in A when grown in LN and HN, respectively. In P species grown under 570 mu mol mol(-1) [CO2], A increased by 16% under HN, but there was no effect in LN. In LS species, the enhancement of A by effect of 760 mu mol mol(-1) [CO2] was 30% and 70% in LN and HN, respectively. The exposure to 570 mu mol mol(-1) [CO2] stimulated A by 31% in HN, but was no effect in LN. Reductions in stomatal conductance (g(s)) and transpiration (E), as a result of elevated [CO2] were observed. Increasing the nutrient supply from low to high increased both the maximum rate of carboxylation (V-cmax) and maximum potential rate of electron transport (J(max)). As the level of [CO2] increased, both the V-cmax and the J(max) were found to decrease, whereas the J(max)/V-cmax ratio increased. In the LS species, the maximum efficiency of PSII (F-v/F-m) was higher in the 760 mu mol mol(-1) [CO2] treatment relative to other [CO2] treatments. The results suggest that when grown under HN and the highest [CO2], the performance of the P species C. urucurana, in terms of photosynthesis and biomass enhancement, is better than the LS species C. legalis. However, a larger biomass is allocated to roots when C. legalis seedlings were exposed to elevated [CO2]. This response would be an important strategy for plant survival and productivity of the LS species under drought stresses conditions on tropical environments in a global-change scenario. (C) 2011 Elsevier B.V. All rights reserved.

Differential regulation of PGC-1α expression in rat liver and skeletal muscle in response to voluntary running

Abstract Background The beneficial actions of exercise training on lipid, glucose and energy metabolism and insulin sensitivity appear to be in part mediated by PGC-1α. Previous studies have shown that spontaneously exercised rats show at rest enhanced responsiveness to exogenous insulin, lower plasma insulin levels and increased skeletal muscle insulin sensitivity. This study was initiated to examine the functional interaction between exercise-induced modulation of skeletal muscle and liver PGC-1α protein expression, whole body insulin sensitivity, and circulating FFA levels as a measure of whole body fatty acid (lipid) metabolism. Methods Two groups of male Wistar rats (2 Mo of age, 188.82 ± 2.77 g BW) were used in this study. One group consisted of control rats placed in standard laboratory cages. Exercising rats were housed individually in cages equipped with running wheels and allowed to run at their own pace for 5 weeks. At the end of exercise training, insulin sensitivity was evaluated by comparing steady-state plasma glucose (SSPG) concentrations at constant plasma insulin levels attained during the continuous infusion of glucose and insulin to each experimental group. Subsequently, soleus and plantaris muscle and liver samples were collected and quantified for PGC-1α protein expression by Western blotting. Collected blood samples were analyzed for glucose, insulin and FFA concentrations. Results Rats housed in the exercise wheel cages demonstrated almost linear increases in running activity with advancing time reaching to maximum value around 4 weeks. On an average, the rats ran a mean (Mean ± SE) of 4.102 ± 0.747 km/day and consumed significantly more food as compared to sedentary controls (P < 0.001) in order to meet their increased caloric requirement. Mean plasma insulin (P < 0.001) and FFA (P < 0.006) concentrations were lower in the exercise-trained rats as compared to sedentary controls. Mean steady state plasma insulin (SSPI) and glucose (SSPG) concentrations were not significantly different in sedentary control rats as compared to exercise-trained animals. Plantaris PGC-1α protein expression increased significantly from a 1.11 ± 0.12 in the sedentary rats to 1.74 ± 0.09 in exercising rats (P < 0.001). However, exercise had no effect on PGC-1α protein content in either soleus muscle or liver tissue. These results indicate that exercise training selectively up regulates the PGC-1α protein expression in high-oxidative fast skeletal muscle type such as plantaris muscle. Conclusion These data suggest that PGC-1α most likely plays a restricted role in exercise-mediated improvements in insulin resistance (sensitivity) and lowering of circulating FFA levels.

Apoptosis rate and transcriptional response of pancreatic islets exposed to the PPAR gamma agonist Pioglitazone

To explore the molecular pathways underlying thiazolidinediones effects on pancreatic islets in conditions mimicking normo- and hyperglycemia, apoptosis rate and transcriptional response to Pioglitazone at both physiological and supraphysiological glucose concentrations were evaluated. Adult rat islets were cultured at physiological (5.6 mM) and supraphysiological (23 mM) glucose concentrations in presence of 10 μM Pioglitazone or vehicle. RNA expression profiling was evaluated with the PancChip 13k cDNA microarray after 24-h, and expression results for some selected genes were validated by qRT-PCR. The effects of Pioglitazone were investigated regarding apoptosis rate after 24-, 48- and 72-h. At 5.6 mM glucose, 101 genes were modulated by Pioglitazone, while 1,235 genes were affected at 23 mM glucose. Gene networks related to lipid metabolism were identified as altered by Pioglitazone at both glucose concentrations. At 23 mM glucose, cell cycle and cell death pathways were significantly regulated as well. At 5.6 mM glucose, Pioglitazone elicited a transient reduction in islets apoptosis rate while at 23 mM, Bcl2 expression was reduced and apoptosis rate was increased by Pioglitazone. Our data demonstrate that the effect of Pioglitazone on gene expression profile and apoptosis rate depends on the glucose concentration. The modulation of genes related to cell death and the increased apoptosis rate observed at supraphysiological glucose concentration raise concerns about Pioglitazone’s direct effects in conditions of hyperglycemia and reinforce the necessity of additional studies designed to evaluate TZDs effects on the preservation of β-cell function in situations where glucotoxicity might be more relevant than lipotoxicity.